Project

Discipline

Cell polarization; Cdc42; Fission yeast; Pheromone; Mating; Microtubules

Lead
Lay summary
Cell polarization is a basic cell biological process necessary for the function of most cells. Classical examples of polarized cells include neurons, with specialized dendrites and axons respectively receiving and transmitting electrical signals, or epithelial cells with specialized surfaces contacting the inside and outside world. In fact, most, if not all cells, even unicellular organisms, are spatially organized in a polarized manner. While eukaryotic cells show a vast diversity of shapes and functions, basic concepts of cell polarization are remarkably conserved. The proposed project uses a simple unicellular model system, the fission yeast Schizosaccharomyces pombe, to study this important problem. The unicellular yeast models have been instrumental in deciphering the mechanisms of cell polarization and establishing basic concepts: Cell polarity is generally initiated by a cell surface landmark, which marks the site towards which the cell orients. The landmark can be positioned either in response to intrinsic signals or in response to extracellular cues. In either case, the landmark then leads to the local activation of a signaling molecule, the small GTPase Cdc42. In turn, Cdc42 activates signaling pathways for cell polarization. One important question is how landmarks recruit Cdc42 for polarization. The project has two broad aims. The first is to dissect how landmarks lead to the local activation of Cdc42 during vegetative growth. Fission yeast cells are rod-shaped, a shape that is maintained by directing growth exclusively to the extremities of the cell. Landmarks are deposited at these locations by the microtubule cytoskeleton. It is however not understood how these connect to Cdc42 and restrict it its local activation at cell extremities. The second broad aim is to establish the fission yeast system as a robust model in which to study pheromone-dependent cell polarization. For sexual reproduction, cells of opposite mating type (sexes) secrete chemo-attractant molecules known as pheromones, which are recognized by potential mates. This induces polarized cell growth in the direction of the mating partner, which ultimately leads to cell fusion and production of highly resistant spores. This process is very poorly studied in fission yeast, which is otherwise an excellent cell biological model system. We will perform genetic screens to search for genes involved in this process. One particular aim will be to reveal how pheromones lead to local Cdc42 activation. In summary, our work will provide novel insights into the initial steps of cell polarization. Since most components important for cell polarization are conserved from yeast to higher eukaryotes, the proposed research is likely to provide general conceptual advance valid beyond the yeast model.

Direct link to Lay Summary

Last update: 21.02.2013

Title	Year

Number	Title	Start	Funding scheme

Cell polarization is a basic cell biological process necessary for the function of most cells. While eukaryotic cells show a vast diversity of shapes and functions, basic concepts of cell polarization are remarkably conserved. Cell polarity is generally initiated by a cell surface landmark, which marks the site towards which the cell orients. The landmark can be positioned either in response to intrinsic signals, often provided by microtubules, or in response to extracellular cues, such as chemo-attractants. This landmark then recruits the small G protein Cdc42, which activates signaling pathways for cell polarization. One important question is how landmarks recruit Cdc42 for polarization. The unicellular yeast models have been instrumental in deciphering the mechanisms of cell polarization and establishing these basic concepts. The current proposal uses the fission yeast to ask how Cdc42 becomes polarized in response to both intrinsic microtubule-dependent cues and extracellular pheromones. There are three specific aims:1. To dissect the microtubule-dependent activation of Cdc42Microtubules define regions of polarization in many cell types, for instance during cell migration or neuronal pathfinding. In fission yeast, microtubules are arranged in a few bundles aligned along the length of the rod-shaped cell and serve to position landmarks at cell ends. These landmarks - the Tea1 and Tea4 proteins - in turn recruit the growth machinery, including Cdc42 for polarized growth at cell tips. This microtubule end-marking system is critical for initiation of growth at the second cell end, a process known as New End Take-Off or NETO. We had previously shown that Tea4 directly binds an actin nucleator of the formin family, For3, and recruits it to the new cell end. How Tea4 promotes Cdc42 activation at the second cell end is however not known. 2. To establish the link between Cdc42 and pheromone signalingPolarization in response to external cues is critical for diverse biological processes, including directional cell migration for wound healing or cellular immune responses. During mating, yeast cells secrete pheromones and respond to their mating partner by polarizing growth in its direction. This pheromone-dependent polarization process depends on G-protein coupled pheromone receptors at the plasma membrane. Work on the distant yeast S. cerevisiae has demonstrated a number of links between the Gß subunit, a scaffold protein Far1, and the Cdc42 activation module. However, the situation in fission yeast is distinct, as the signal is transmitted through Ga not Gß and there is no Far1 homologue. How Cdc42 is recruited to the incipient mating projection site is unknown.3. To perform a systematic analysis of pheromone-dependent cell polarizationOur aim is to establish fission yeast mating as a robust model in which to study pheromone-dependent cell polarization. Perhaps surprisingly, this field is currently vastly understudied, despite the wide range of genetic, genomic, biochemical and imaging tools offered by the fission yeast system. We expect our findings to provide novel concepts in extracellular cue-induced cell polarization.In summary, our work will provide novel insights into the initial steps of cell polarization. Since most components important for cell polarization are conserved from yeast to higher eukaryotes, the proposed research is likely to provide general conceptual advance valid beyond the yeast model.